Despite the fact that they are immunologically foreign, placental mammals do not recognize and reject their babies. Clearly, "failure" of the mother to reject the fetus is essential to life and yet, despite more than fifty years of active research, there are still many mysteries surrounding maternal-fetal immune tolerance. Among the many factors that may play a role in establishing immune tolerance of the fetus, one of the most likely to be critical relates to the expression of the Major Histocompatibility molecules Type I and II (MHC I and II) in the extra-embryonic structures that come into direct contact with the maternal immune system. In particular, it has been noted that the trophoblast does not express MHC II, and it has been suggested that this lack is crucial to maternal tolerance. Although this theory is intriguing, it has never been experimentally tested. We propose to use a novel method that utilizes lentivirus in to manipulate gene expression in extraembryonic tissues in order to force the aberrant expression of MHC II surface antigens at the maternal-fetal interface in mice. By so doing, we will establish an experimental system that will allow us to fully explore whether the lack of MHC II in the trophoblast is critical to successful pregnancy. We anticipate that these experiments will ultimately lead to a major advance in understanding maternal-fetal immune tolerance. This, in turn, will be relevant to understanding and treating immune-mediated pregnancy failure. More broadly, an improved understanding of immune tolerance will be relevant in transplantation biology and cancer immunology as well. PUBLIC HEALTH RELEVANCE: Maternal immune tolerance of the fetus is poorly understood. The present proposal is aimed at using a novel technology in order to test a major but unproven theory of how the fetus is immunologically tolerated by the mother. The results of this work are expected to have major significance for reproductive immunology as well as for transplant and cancer biology.